Sordarin is an antifungal antibiotic isolated from the mould Sordaria araneosa (see GB 1,162,027 and Helvetica Chimica Acta, 1971, 51:119-20). Other compounds having the sordarin skeleton have also been reported as antifungal agents. Japanese Kokai J62040292 discloses the compound zofimarin isolated from Zofiela marina sp.; Japanese Kokai J06157582 discloses the compound BE-31405 isolated from Penicillium sp.; and SCH57404 is reported in J. Antibiotics, 1995, 48:1171-1172. Semi-synthetic sordarin derivatives are reported in PCT Applications WO96/14326 and WO96/14327.
Sordaricin, the aglycone, may be obtained from sordarin by acid hydrolysis (Hauser and Sigg, Helvetica Chimica Acta, 1971, 51:119-20). The total synthesis of sordaricin methyl ester is reported in Kato et al., J. Chem. Soc., Chem. Commun., 1993, 1002-1004, which also discloses o-methoxymethyl sordaricin methyl ester. The diacetate of 4-deformyl-4-hydroxymethyl sordaricin is disclosed in Mander and Robinson, J. Org. Chem., 1991, 56(11):3395-3601. Neither sordaricin nor the reported derivatives thereof has been shown to have biological activity.
Balkovec et al. (U.S. Pat. Nos. 6,040,463 and 6,136,853) discloses a compound of sordarin derivative.
Nielsen-Kahn et al. (U.S. Pat. No. 5,972,996) and Tse, Bruno (U.S. Pat. No. 5,965,612) disclose a compound of 4-cyano-4-deformylsordarin derivatives.
Sturr et al. (U.S. Pat. No. 6,228,622) discloses a compound of C11-hydroxysodarin and a process for producing it using Actinomyces spp, (Merck Culture Collection MA7235) by a biotransformation.
An objective of the present invention is to provide a novel class of sordarin analogues derived from C-11-hydroxysordarin that are potent antifungal agents for general use and against pathogens associated with human and agricultural fungal infections.